87-LB: Binding Kinetics, Bias, Receptor Internalization, and Effects on Insulin Secretion for a Novel GLP1R-GIPR Dual Agonist, HISHS-2001

Autor:	Rajamannar Thennati, Vinod Burade, Zenouska Ramchunder, Alejandra Tomas, Guy A. Rutter, Ben Jones, Gaelle Carrat, Isabelle Leclerc, Yusman Manchanda, Piero Marchetti
Rok vydání:	2021
Předmět:	Agonist endocrine system medicine.medical_specialty Gs alpha subunit Chemistry medicine.drug_class Endocrinology Diabetes and Metabolism Semaglutide Incretin Endocrinology Internal medicine Internal Medicine medicine Potency Receptor Beta (finance) Lipid raft
Zdroj:	Diabetes. 70
ISSN:	1939-327X 0012-1797
DOI:	10.2337/db21-87-lb
Popis:	Background and Aims: To characterize a novel incretin analogue which engages glucagon-like peptide-1 (GLP1R) and glucose-dependent insulinotropic peptide (GIPR) receptors. Methods: Potencies for cAMP production were determined at GLP-1R and GIPR in Flp-In T-REx-293 cells. Assessment of SNAP-tagged GLP-1R internalisation by confocal microscopy, incorporation of GLP-1R into lipid rafts, Gs recruitment to GLP-1R and GIPR with NanoBiT™ used INS-1(832/3) beta cells. Ca2+ responses were recorded in mouse islets by time-lapse confocal microscopy using Cal520 AM. Results: HISHS-2001 displayed higher potency versus tirzepatide for cAMP production at both receptors (Table). GLP-1R beta arrestin-2 recruitment was lower with HISHS-2001, indicating increased bias. Efficacy and potency of recruitment of Gs protein to the GLP-1R were lower for HISHS-2001 vs. tirzepatide (Table). HISHS-2001 showed increased potency for Gs recruitment to the GIPR. GLP-1R endocytosis was lower for HISHS-2001 vs. tirzepatide but both agonists showed increased recruitment of GLP-1R to lipid rafts vs. semaglutide. Ca2+ responses, and potentiation of insulin secretion from mouse islets tended to be higher for HISHS-2001 vs. tirzepatide. Both displayed enhanced insulin secretion from human islets vs. semaglutide (Table). Conclusions: HISHS-2001 may provide a useful new GLP1R-GIP dual agonist. Disclosure Y. Manchanda: None. G. A. Rutter: Advisory Panel; Self; Sun Pharmaceutical Industries Ltd. B. Jones: Research Support; Self; Sun Pharmaceutical Industries Ltd. G. Carrat: None. Z. Ramchunder: None. P. Marchetti: Consultant; Self; Menarini Group. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. R. Thennati: None. V. S. Burade: None. A. Tomas: Other Relationship; Self; Sun Pharmaceutical Industries Ltd. Funding Sun Pharmaceutical Industries Ltd. (P79787)
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::b1ecb4817dd9756a9a057090dc595ff0 https://doi.org/10.2337/db21-87-lb Zobrazit plný text záznamu